Association between augmented renal clearance and clinical outcomes in patients receiving β-lactam antibiotic therapy by continuous or intermittent infusion: A nested cohort study of the BLING-II randomised, placebo-controlled, clinical trial

Andrew A. Udy, Joel M. Dulhunty, Jason A. Roberts, Joshua S. Davis, Steven A R Webb, Rinaldo Bellomo, Charles Gomersall, Charudatt Shirwadkar, Glenn M. Eastwood, John A. Myburgh, David L. Paterson, Therese Starr, Sanjoy K. Paul, Jeffrey Lipman

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    Abstract

    Augmented renal clearance (ARC) is known to influence β-lactam antibiotic pharmacokinetics. This substudy of the BLING-II trial aimed to explore the association between ARC and patient outcomes in a large randomised clinical trial. BLING-II enrolled 432 participants with severe sepsis randomised to receive β-lactam therapy by continuous or intermittent infusion. An 8-h creatinine clearance (CLCr) measured on Day 1 was used to identify ARC, defined as CLCr ≥ 130 mL/min. Patients receiving any form of renal replacement therapy were excluded. Primary outcome was alive ICU-free days at Day 28. Secondary outcomes included 90-day mortality and clinical cure at 14 days following antibiotic cessation. A total of 254 patients were included, among which 45 (17.7%) manifested ARC [median (IQR) CLCr 165 (144-198) mL/min]. ARC patients were younger (P <0.001), more commonly male (P = 0.04) and had less organ dysfunction (P <0.001). There was no difference in ICU-free days at Day 28 [ARC, 21 (12-24) days; no ARC, 21 (11-25) days; P = 0.89], although clinical cure was significantly greater in the unadjusted analysis in those manifesting ARC [33/45 (73.3%) vs. 115/209 (55.0%) P = 0.02]. This was attenuated in the multivariable analysis. No difference was noted in 90-day mortality. There were no statistically significant differences in clinical outcomes in ARC patients according to the dosing strategy employed. In this substudy of a large clinical trial of β-lactam antibiotics in severe sepsis, ARC was not associated with any differences in outcomes, regardless of dosing strategy.

    Original languageEnglish
    Article number624-630
    Number of pages7
    JournalInternational Journal of Antimicrobial Agents
    Volume49
    Issue number5
    DOIs
    Publication statusPublished - May 2017

    Fingerprint

    Lactams
    Cohort Studies
    Randomized Controlled Trials
    Placebos
    Anti-Bacterial Agents
    Kidney
    Therapeutics
    Sepsis
    Renal Replacement Therapy
    Mortality
    Creatinine
    Pharmacokinetics
    Clinical Trials

    Cite this

    Udy, Andrew A. ; Dulhunty, Joel M. ; Roberts, Jason A. ; Davis, Joshua S. ; Webb, Steven A R ; Bellomo, Rinaldo ; Gomersall, Charles ; Shirwadkar, Charudatt ; Eastwood, Glenn M. ; Myburgh, John A. ; Paterson, David L. ; Starr, Therese ; Paul, Sanjoy K. ; Lipman, Jeffrey. / Association between augmented renal clearance and clinical outcomes in patients receiving β-lactam antibiotic therapy by continuous or intermittent infusion : A nested cohort study of the BLING-II randomised, placebo-controlled, clinical trial. In: International Journal of Antimicrobial Agents. 2017 ; Vol. 49, No. 5.
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    abstract = "Augmented renal clearance (ARC) is known to influence β-lactam antibiotic pharmacokinetics. This substudy of the BLING-II trial aimed to explore the association between ARC and patient outcomes in a large randomised clinical trial. BLING-II enrolled 432 participants with severe sepsis randomised to receive β-lactam therapy by continuous or intermittent infusion. An 8-h creatinine clearance (CLCr) measured on Day 1 was used to identify ARC, defined as CLCr ≥ 130 mL/min. Patients receiving any form of renal replacement therapy were excluded. Primary outcome was alive ICU-free days at Day 28. Secondary outcomes included 90-day mortality and clinical cure at 14 days following antibiotic cessation. A total of 254 patients were included, among which 45 (17.7{\%}) manifested ARC [median (IQR) CLCr 165 (144-198) mL/min]. ARC patients were younger (P <0.001), more commonly male (P = 0.04) and had less organ dysfunction (P <0.001). There was no difference in ICU-free days at Day 28 [ARC, 21 (12-24) days; no ARC, 21 (11-25) days; P = 0.89], although clinical cure was significantly greater in the unadjusted analysis in those manifesting ARC [33/45 (73.3{\%}) vs. 115/209 (55.0{\%}) P = 0.02]. This was attenuated in the multivariable analysis. No difference was noted in 90-day mortality. There were no statistically significant differences in clinical outcomes in ARC patients according to the dosing strategy employed. In this substudy of a large clinical trial of β-lactam antibiotics in severe sepsis, ARC was not associated with any differences in outcomes, regardless of dosing strategy.",
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    Association between augmented renal clearance and clinical outcomes in patients receiving β-lactam antibiotic therapy by continuous or intermittent infusion : A nested cohort study of the BLING-II randomised, placebo-controlled, clinical trial. / Udy, Andrew A.; Dulhunty, Joel M.; Roberts, Jason A.; Davis, Joshua S.; Webb, Steven A R; Bellomo, Rinaldo; Gomersall, Charles; Shirwadkar, Charudatt; Eastwood, Glenn M.; Myburgh, John A.; Paterson, David L.; Starr, Therese; Paul, Sanjoy K.; Lipman, Jeffrey.

    In: International Journal of Antimicrobial Agents, Vol. 49, No. 5, 624-630, 05.2017.

    Research output: Contribution to journalArticle

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    T2 - A nested cohort study of the BLING-II randomised, placebo-controlled, clinical trial

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    AU - Dulhunty, Joel M.

    AU - Roberts, Jason A.

    AU - Davis, Joshua S.

    AU - Webb, Steven A R

    AU - Bellomo, Rinaldo

    AU - Gomersall, Charles

    AU - Shirwadkar, Charudatt

    AU - Eastwood, Glenn M.

    AU - Myburgh, John A.

    AU - Paterson, David L.

    AU - Starr, Therese

    AU - Paul, Sanjoy K.

    AU - Lipman, Jeffrey

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    N2 - Augmented renal clearance (ARC) is known to influence β-lactam antibiotic pharmacokinetics. This substudy of the BLING-II trial aimed to explore the association between ARC and patient outcomes in a large randomised clinical trial. BLING-II enrolled 432 participants with severe sepsis randomised to receive β-lactam therapy by continuous or intermittent infusion. An 8-h creatinine clearance (CLCr) measured on Day 1 was used to identify ARC, defined as CLCr ≥ 130 mL/min. Patients receiving any form of renal replacement therapy were excluded. Primary outcome was alive ICU-free days at Day 28. Secondary outcomes included 90-day mortality and clinical cure at 14 days following antibiotic cessation. A total of 254 patients were included, among which 45 (17.7%) manifested ARC [median (IQR) CLCr 165 (144-198) mL/min]. ARC patients were younger (P <0.001), more commonly male (P = 0.04) and had less organ dysfunction (P <0.001). There was no difference in ICU-free days at Day 28 [ARC, 21 (12-24) days; no ARC, 21 (11-25) days; P = 0.89], although clinical cure was significantly greater in the unadjusted analysis in those manifesting ARC [33/45 (73.3%) vs. 115/209 (55.0%) P = 0.02]. This was attenuated in the multivariable analysis. No difference was noted in 90-day mortality. There were no statistically significant differences in clinical outcomes in ARC patients according to the dosing strategy employed. In this substudy of a large clinical trial of β-lactam antibiotics in severe sepsis, ARC was not associated with any differences in outcomes, regardless of dosing strategy.

    AB - Augmented renal clearance (ARC) is known to influence β-lactam antibiotic pharmacokinetics. This substudy of the BLING-II trial aimed to explore the association between ARC and patient outcomes in a large randomised clinical trial. BLING-II enrolled 432 participants with severe sepsis randomised to receive β-lactam therapy by continuous or intermittent infusion. An 8-h creatinine clearance (CLCr) measured on Day 1 was used to identify ARC, defined as CLCr ≥ 130 mL/min. Patients receiving any form of renal replacement therapy were excluded. Primary outcome was alive ICU-free days at Day 28. Secondary outcomes included 90-day mortality and clinical cure at 14 days following antibiotic cessation. A total of 254 patients were included, among which 45 (17.7%) manifested ARC [median (IQR) CLCr 165 (144-198) mL/min]. ARC patients were younger (P <0.001), more commonly male (P = 0.04) and had less organ dysfunction (P <0.001). There was no difference in ICU-free days at Day 28 [ARC, 21 (12-24) days; no ARC, 21 (11-25) days; P = 0.89], although clinical cure was significantly greater in the unadjusted analysis in those manifesting ARC [33/45 (73.3%) vs. 115/209 (55.0%) P = 0.02]. This was attenuated in the multivariable analysis. No difference was noted in 90-day mortality. There were no statistically significant differences in clinical outcomes in ARC patients according to the dosing strategy employed. In this substudy of a large clinical trial of β-lactam antibiotics in severe sepsis, ARC was not associated with any differences in outcomes, regardless of dosing strategy.

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